tbuckley/cabot-search huggingface dataset:
DIPG-43. Glucosylceramide synthase inhibitors induce ceramide accumulation and sensitise H3K27 Mutant Diffuse midline Glioma to irradiation
Authors: Claudia Paret, Roger Sandhoff, Sebastian Zahnreich, Pia Charlotte Wehling, Khalifa El Malki, Jörg Faber
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND AND AIMS: Glycosphingolipids (GSL) are amphipathic lipids particularly abundant in the brain where their amount and expression patterns change drastically during the embryonic to postnatal stages and during tumorigenesis. The biosynthesis of GSL begins with the formation of glucosylceramide from ceramide, a step catalysed by the glucosylceramide synthase (UGCG). UGCG can be inhibited by eliglustat, which is used for treating children with Gaucher‘s disease. We have previously shown that the GSL composition is deregulated in H3K27M mutant diffuse midline glioma (H3K27M mut) and that eliglustat inhibits cell proliferation. Here we analysed the mechanism of action of eliglustat in H3K27M mut and its effect on irradiation. METHODS: The concentration of different components of the sphingolipid metabolism (ceramide, ceramide-1-Phosphate (CIP), sphingomyelin, Sphingosine and Sphingosine-1-Phosphate (S1P)) was assessed by mass spectrometry in the H3K27M mut cell line SF8628, before and after treatment with eliglustat. The combination of eliglustat with ionizing radiation was analysed by clonogenic assay. RESULTS: The treatment of H3K27M mut cells with eliglustat resulted in a significant increase in the concentration of ceramide, Sphingosine, C1P, but not S1P. The increase was concentration and time dependent and was not observed after longer incubation. Eliglustat treatment reduced the colony formation ability after irradiation. CONCLUSIONS: Ceramide is a known mediator of apoptosis involved in the molecular mechanisms underlying cellular response to irradiation. Increased endogenous ceramide levels, induced by blocking the synthesis of GSL, may sensitize H3K27M mut cells to irradiation. However, ceramide can be converted in C1P, a potent inhibitor of apoptosis and inducer of cell survival. Thus, the time and concentration dependent shift to ceramide and C1P requires further investigation in order to achieve an appropriate balance between the levels of these two metabolites and identify the optimal therapeutic window for combination with irradiation and potentially chemotherapy
Comparative effectiveness of teclistamab versus real-world treatments for patients with triple-class exposed (TCE), relapsed/refractory multiple myeloma (RRMM).
Authors: Amrita Y. Krishnan, Ajay K. Nooka, Ajai Chari, Alfred L. Garfall, Thomas G. Martin, Sandhya Nair, Xiwu Lin, Keqin Qi, Anil Londhe, Lixia Pei, Eric Ammann, Rachel Kobos, Jennifer Smit, Trilok V. Parekh, Mary Slavcev, Saad Zafar Usmani
Journal: Journal of Clinical Oncology (2022)

8036 Background: Teclistamab is a B-cell maturation antigen × CD3 bispecific antibody currently being evaluated in MajesTEC-1 (NCT04557098), an open-label, single-arm, phase 1/2 trial in patients with RRMM who had received ≥3 prior lines of therapy (LOT) and were TCE to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Given the absence of a control arm in MajesTEC-1, we assessed the comparative effectiveness of teclistamab versus treatment regimens using an external control arm from a real-world database. Methods: An external control arm for MajesTEC-1 was created from eligible patients in the nationwide de-identified electronic health record-derived Flatiron Health multiple myeloma cohort database who started a new line of therapy (physician’s choice) following triple-class exposure between January 2011 and August 2021, received ≥3 prior LOT, and satisfied key MajesTEC-1 eligibility criteria. Individual patient data from MajesTEC-1 included patients who received teclistamab (1.5 mg/kg weekly) at a clinical cutoff of Sep 7, 2021. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances in baseline covariates of prognostic significance: refractory status, progression on last LOT, cytogenetic risk, International Staging System stage, number of prior LOT, time since diagnosis, age, and hemoglobin. Outcomes of interest included progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS); these outcomes were analyzed as time-to-event data using IPTW adjusted Kaplan-Meier estimates and a weighted Cox proportional hazards model. Several sensitivity analyses were conducted. Results: After IPTW, baseline characteristics were comparable between the 2 cohorts. Patients treated with teclistamab had improved PFS (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.32–0.59; P&lt; 0.0001), TTNT (HR 0.42; 95% CI 0.31–0.58; P&lt; 0.0001), and OS (HR 0.73; 95% CI 0.48–1.09; P= 0.13) versus assessed real-world treatments. Results were similar for all sensitivity analyses. Conclusions: Teclistamab showed improved effectiveness for PFS, TTNT, and OS, compared with real-world treatments used in patients with TCE RRMM who received ≥3 prior LOT. These findings highlight the therapeutic potential of teclistamab in patients with RRMM who have limited treatment options.
Mobile app in oncology: A pilot survey on Latina patients with gynecological cancers and their perception on utilizing a mobile app.
Authors: Paulina Ramirez, Eugene Patrick Toy, Suzanne Lababidi, Harvey Greenberg, Christina Bracamontes, Angela Jones, Zuber D. Mulla, Jennifer L. Brown
Journal: Journal of Clinical Oncology (2022)

1571 Background: Mobile applications have changed the way that users access information and revolutionized healthcare by allowing patients to educate themselves regarding their diagnosis and treatment. Challenges in developing a mobile health application include patient satisfaction and usage over time. Barriers to usage include trust, personalization, and accessibility. Investigating the patient population’s preferences on app content and ease of use is imperative. The use of mobile applications specifically for Latina Gynecologic Oncology patients undergoing treatment has yet to be investigated. Methods: Fifty-six patients were recruited from the Gynecologic Oncology clinic at an urban academic health sciences center located on the Texas-Mexico border. Cross-sectional analyses were performed. Subjects were asked a series of 10-point Likert scale questions including how comfortable they would feel using medical applications on their smartphones. Linear regression models were fit with this scale score as the outcome. Results: The age of the 56 patients ranged from 28 to 77 years with a mean of 53.9 years (SD: 11.1). Spanish was the preferred language of 53.8% of the patients (28/52). Forty-four subjects were available for the regression analyses. Subjects were asked, “Would you feel comfortable using medical applications on your smartphone,” where 1 represented “not at all comfortable” and 10 represented “very comfortable”. The mean comfort scale score was 7.39 (SD: 2.85). Thirty of the 44 subjects (68.2%) replied “Multiple times per day” to the question about how frequently they use mobile apps on their phone. After controlling for the patient’s age in a regression model, patients who used mobile apps multiple times per day had an average comfort scale score that was 1.75 points higher than that of women who did not use mobile apps on their phone multiple times per day (p = 0.03). After adjusting for the frequency of mobile app use, there was a reduction of 0.11 points (p = 0.002) in the comfort scale score for every one year increase in the patient’s age. Conclusions: Our unique pilot study found a positive association between the frequency of current app use and anticipated comfort in using smartphone medical applications. Overall, patients demonstrated a considerable amount of comfort with the prospect of using a mobile app. These findings support the idea of creating a mobile app designed to monitor Latina Gynecologic Oncology patients in efforts to lessen patients’ postoperative burden, improve mortality and morbidity outcomes, and decrease health care system costs.[Table: see text]
Correlation between homologous recombination repair gene mutation and immunotherapy efficacy in patients with advanced melanoma.
Authors: Changxuan You, Chengzhi Zhou, Zhixuan You, Meng Lv, Xuanyu He, Yingqin Pan, Junfeng Ge, Xue Hu, Yating Zheng, Mengli Huang
Journal: Journal of Clinical Oncology (2022)

e21551 Background: Nowadays, immunotherapy targeting immune checkpoint receptors is one of the cornerstones of systemic treatment in melanoma. Homologous recombination repair (HRR) was a pathway of the DNA damage response (DDR), has been shown to be associated with the efficacy of platinum-based chemotherapy, PARP inhibitor therapy and immunotherapy in variety of cancers. However, their predictive value of HRR remained unknown in patients with advanced melanoma. Methods: An independent cohort (Samstein2018) with data from 99 patients with advanced melanoma were used to analyze the correlation with immunogenic marker the prognostic effect of HRR on immunotherapy, and another four cohorts (Miao2018, Allen 2015, Hugo2016, and Synder2014) are used for validation. Immune filtration cells scores analyzed by the TCGA-SKCM cohort were used to explore potential mechanisms related to the immune microenvironment. Results: Compared to patients with HRR pathway wild-type (HRRwt), those with HRR mutations (HRRmut) in an independent anti-CTLA-4-treated cohort had higher tumor mutation burden (TMB; median: 29.55Muts/Mb versus 4.46Muts/Mb; P = 0.0003), objective response rates (ORR; P = 0.007), and longer overall survival (OS; median: 58 versus 22 months, hazard ratio (HR) = 2.4, 95%CI 1.17-4.92, P = 0.014). These findings were further validated in a pooled anti-CTLA-4-treated cohort in terms of the ORR and OS. However, there was no correlation between HRRmut and OS in the anti-PD-1-treated cohort. Subgroup analysis showed that although patients with HRRmut received the same benefits from anti-CTLA-4 and anti-PD-1/L1 therapy (p = 0.59), the value of anti-CTLA-4 therapy in the HRRmut group was similar or even better than that in the anti-PD-1/L1 therapy group (24.1 months vs 22.7 months), which unlike it in the HRRwt group (10.8 months vs 32.0 months). In addition, transcriptome profiling analysis revealed that 44 (66.7%) genes mutation of HRR pathway associated with reshaping of the immunological microenvironment in melanoma tumors. Conclusions: HRRmut were associated with a higher TMB level, and immunotherapeutic effect. HRR may serve as an independent predictor of anti-CTLA-4 therapy efficacy in patients with advanced melanoma and their clinical value warrants further investigation.
LGG-09. A Nationwide Service Evaluation of Safety, Radiologic and Visual Outcome Refining Bevacizumab-based Treatments in Children with Progressive Low-Grade Glioma
Authors: Katherine Green, Paraskevi Panagopoulou, Felice D’Arco, Patricia O'Hare, Richard Bowman, Bronwen Walters, Christine Dahl, Mette Jorgensen, Pritesh Patel, Olga Slater, Rehana Ahmed, Simon Bailey, Fernando Carceller, Rhiannon Collins, Elizabeth Corley, Martin English, James Hayden, Lisa Howells, Ahmed Kamal, John Paul Kilday, Stephen Lowis, Blanche Lumb, Thomas Micic, Dip Mitra, Erika Pace, Susan Picton, Barry Pizer, Ayad Shafiq, Lena Uzunova, Shaun Wilson, Harriet Wayman, Darren Hargrave, Enrico Opocher
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Bevacizumab/Irinotecan is currently 3rd-line treatment in the UK for progressive Paediatric Low-Grade Glioma (PLGG) based on limited evidence. A nationwide service evaluation was conducted to review its safety and efficacy amongst a larger cohort. METHODS: Data from children with PLGG receiving Bevacizumab-based Treatments (BBT) from 11 UK Centres (2009-2020) were reviewed. Radiological and visual outcomes were based on standardized measurements. Clinical-radiological correlation was investigated. Time to progression from BBT stop, progression free-survival (PFS) curves and multivariate analysis of prognostic factors (p 0.05) were performed. RESULTS: 88 children with PLGG (88% OPG, 24% NF1) had BBT for radiological (43%), visual (20%) or combined (27%) progression, after 40 months (median) from diagnosis. Amongst OPG cases, visual acuity (VA) per eye (better/worse) before BBT was logMAR 0.0-0.3 (23/7) 0.3 - 1.0 (27/20), &amp;gt; 1.0 (14/18) and LP/NLP (8/27), with 19/8 children respectively blind (LP/NLP) in one or both eyes. Bevacizumab 10 mg/kg every 14 days (median 24 doses) was given as 3rd line+ with Irinotecan (85%) or alongside 1st/2nd line chemo (15%) leading to remarkable radiological (88%) and visual (74%) responses (stable or improved) within 3-6 months, with limited toxicity. 12% progressed on treatment, and 8% died unrelated to BBT. After initial response 65% progressed at a median of 8 months (4 - 23) after BBT, resulting in 3-year-all-causes-PFS of 16% and 3-yr-visual-PFS of 45% from start of BBT. Visual concordance with MRI was poor (36%) but increases (47%) when better-eye determines visual outcome. Lack of NF1 and diencephalic syndrome (DS) at presentation were independent negative prognostic factors for PFS. CONCLUSIONS: A remarkable but transient effect of BBT has been confirmed. Visual &amp;gt; radiological responses can be sustained after BBT. Variations in current BBT strategies justifies further research, including the potential upfront use alongside conventional first-line chemotherapy as sight-saving strategy.
Retrospective analysis of vaccine antibody titers in patients with different stages of monoclonal plasma cell disorders.
Authors: Alankrita Taneja, Sarah Parker, Sheeba Habeeb Ba Aqeel, Kristopher Attwood, Jens Hillengass
Journal: Journal of Clinical Oncology (2022)

e20031 Background: Infections occur with up to twofold increased risk in patients with monoclonal gammopathy of undetermined significance (MGUS) and tenfold increased risk in multiple myeloma (MM). To reduce risk, revaccination following autologous hematopoietic cell transplantation (AHCT) is recommended to restore humoral immunity. We have previously shown that vaccine titers after AHCT have prognostic significance. In the COVID era, reliable clinical data about antibody titers is relevant yet scarce. We investigated the significance of different vaccine titers in newly diagnosed patients in different stages of the disease. Methods: The study population comprised of 77 patients with MGUS, smoldering multiple myeloma (SMM) and MM who were seen at a tertiary cancer center from 2018-2022. All patients had antibody titers (B. pertussis, Diptheria, H. Influenzae B, Hepatitis, Influenza, Meningitis, Mumps, Rubeola, Rubella, Poliovirus, S. pneumoniae, Varicella Zoster and Tetanus) tested at the time of diagnosis, prior to start of treatment if indicated. Titers were interpreted in accordance with the manufacturers’ recommendations. Patient characteristics were compared using the Kruskal-Wallis and Fisher’s exact tests. Associations with % titer positivity were evaluated using the Kruskal-Wallis test. Results: There was significant difference in antibody titer positivity between the different patient groups (51.4% in MGUS, 40.5% in SMM and 34.2% in MM) (p &lt; 0.001). There was no difference in antibody titer positivity depending on age, sex or race. Among individual pathogens, there was a significant difference between the three groups in regards to titers for Diphtheria, Mumps, Poliovirus 3, Strep pneumoniae 19, Strep pneumoniae 56 and Varicella Zoster. Conclusions: Antibody titers for vaccine preventable diseases are significantly different between patients with MGUS, SMM and MM at the time of diagnosis, with MGUS having the highest and MM having the lowest positivity. Patient related factors such as age, sex or race were not associated with antibody titer positivity. Current guidelines for revaccination are not extended to patients with MGUS and SMM and can be considered in prospective trials.[Table: see text]
CAR T-cells effective for post-CART relapse: A new treatment paradigm.
Authors: Elizabeth M. Holland, Bonnie Yates, Sara K. Silbert, Toni Foley, Lauren Little, Terry J. Fry, Steven Highfill, David Stroncek, Haneen Shalabi, Nirali N. Shah
Journal: Journal of Clinical Oncology (2022)

e19508 Background: Chimeric antigen receptor T-cells (CART) induce remarkable responses in B-cell acute lymphoblastic leukemia (B-ALL), but relapse remains a challenge. Effective therapies for post-CART relapse are limited but may include infusion of a unique CART construct, a strategy distinct from reinfusion of the same CART product. Given limited data evaluating outcomes of a unique CART as salvage therapy for post-CART relapse, we report on the impact of prior CART constructs on subsequent CART responses. Methods: This was a retrospective review (NCT03827343) of children and young adults receiving CD19 and/or CD22 CART therapy for B-ALL between 7/1/12-12/30/21 at our center. Patients included received at least 2 unique CART constructs at some point in therapy, excluding interim CART reinfusions. CART-A was the first CART construct ever received and CART-B the second unique CART. The primary objective was to evaluate complete remission (CR) rates following CART-A versus CART-B. Results: Of 135 heavily pretreated patients, 54 (40%) received at least one prior CART. The majority (n=37, 68.5%) were male. Median age at CART-A and CART-B was 12.5 (range, 3.3-30.4) and 13.7 years (range, 4.5-30.7), respectively. In 42 (77.8%) patients, CART-B targeted a different antigen than CART-A, primarily due to loss of antigen target after CART-A. CR rate was substantially lower with CART-B (n=35, 64.8%) than with CART-A (n=48, 88.9%, p=0.006) (Table). Still, two (3.7%) patients with CART-A nonresponse attained CR with CART-B. Most CART-B responders (n=31, 88.6%) had CART-B targeting a different antigen than CART-A, suggesting limitations of same antigen targeting even with a unique CART construct. CART-B responses amongst 10 patients with interim hematopoietic stem cell transplantation (HSCT) after CART-A were similar to CART-B responses in those without interim HSCT (5 of 10, 50% vs. 30 of 44, 68.2%, p=0.3). In those where CRS grade was known for both CART infusions (n=40), CRS severity was milder with CART-B (≥grade 3, n=1, 2.5%) than with CART-A (≥grade 3, n=15, 37.5%, p=0.0001). Conclusions: Using an alternative CART for post-CART relapse is effective in a substantial proportion of patients, particularly when targeting a unique antigen. As post-CART relapse occurs more frequently and patients receive multiple CARTs, identifying optimization strategies for CART-B will be critical. Further investigation of indication for CART-B, role of interim HSCT, and optimal timing for sequential CART infusions is underway.[Table: see text]
Screening of FGFR patients for FGFR directed clinical trials in Network Genomic Medicine (NGM): Real-world data.
Authors: Heather Scharpenseel, Florian Malchers, Inken Terjung, Axel Hillmer, Sabine Merkelbach-Bruse, Andreas H. Scheel, Janna Siemanowski, Matthias Scheffler, Richard Riedel, Anna Eisert, Sebastian Yves Friedrich Michels, Rieke Nila Fischer, Jan-Philip Weber, Theresa Westphal, Anna Kron, Juliane Sueptitz, Roman K. Thomas, Reinhard Buettner, Juergen Wolf, Lucia Nogova
Journal: Journal of Clinical Oncology (2022)

e21013 Background: The fibroblast growth factor receptor (FGFR) 1-4 genes show a heterogenic landscape of alterations in non-small cell lung cancer (NSCLC) whereas only a small amount is yet considered to have oncogenic potential. The frequency of activating FGFR alterations is low, counting for approximately 2% of NSCLC. We have screened NSCLC patients (pts) for FGFR translocations/mutations within NGM and analysed them on FGFR alteration frequency, patient characteristics and outcome. Methods: From 04/2019 to 01/2020 we screened 472 squamous NSCLC for FGFR gene alterations and from 02/2020 to 12/2021 an additional 5286 patients including all NSCLC cases. Of these 5286 pts, 1097 pts were analysed for FGFR fusions. We used DNA-NGS for FGFR-mutations and RNA-NGS for FGFR–translocations. Activating mutations were defined according to the publicly available molecular data bases and published data. Results: Within the cohort of 5758 NSCLC patients, we found 316 (5.5%) patients with FGFR alterations. Sixty-six (20.9% of FGFR, 1.1% of NSCLC) patients had alterations classified as activating, of whom 39 had FGFR point mutations and 27 FGFR translocations. Concerning the patients with activating alterations, they had UICC stage III or IV at time of diagnosis; 22 were females; 58 patients had squamous cell carcinoma, 6 patients had adenocarcinoma and 2 had large cell neuroendocrine carcinoma. Fifty-three patients (80.3%) with activating FGFR alteration had a co-mutation: TP53 (inactivating) co-mutation was seen in 41 cases (62.1%) and 19 cases had either PTEN (7 pts), KRAS (4), EGFR (3), PIK3CA (2), ROS1 (1), ALK (1) or BRAF (1) mutations. Ten patients were included in a FGFR-targeted trial. Sixty patients were available for follow-up. The median overall survival (mOS) was 21.4 month (95%CI: 16.8–25.9) for all patients with activating FGFR alteration, whereas mOS was 18.5 month (95%CI: 13.2-23.9) for FGFR mutation and 25.3 months (95%CI: 17.8-32.9) for FGFR fusions. Conclusions: FGFR 1-4 gene alterations are rare. Large molecular and clinical networks are necessary to identify these pts. Prognostic factors of FGFR patients are currently not defined. Further assessments on molecular and clinical features in FGFR altered NSCLC are needed to identify sensitivity to FGFR inhibition. Clinical trials with specific FGFR inhibitors are ongoing.